Flaws in methods of evidence-based medicine may adversely affect public health directives.
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Evidence-Based Medicine↗
Biomedical subjects
J G Kral
Publications and source records attributed to J G Kral.
Evidence-based medicine reports on obesity surgery: a critique.
OBJECTIVE: To evaluate evidence in recent authoritative 'Evidence-Based Medicine' (EBM) reports on surgery for severe obesity. METHODS: Focused review of Index Medicus citations and authors' own databases of publications on surgery for obesity, 1978-2004. RESULTS: EBM criteria for assessment of strength of evidence requiring randomized controlled studies (RCTs) in these reports are inappropriate for evaluating invasive treatments such as surgery, which have robust physiological effects, are difficult to reverse and may have more serious side effects than the drug studies for which the criteria were promulgated. Flaws in these reports include omissions of important studies demonstrating improvements in comorbidity, factual errors in descriptions of operations and faulty analyses of outcomes of laparoscopic approaches. There are misinterpretations of cited papers, and inclusion of obsolete operations as well as a study generated during the 'learning curve' of an avowed complex procedure. CONCLUSION: EBM analyses of surgical modalities affecting access to care require relevant evaluation criteria, true peer review and expert consultation. Authors' claims of objectivity by invoking use of evidence-based criteria applicable to drug treatment and other easily reversible forms of therapy are questionable. Decisions based on flawed EBM reports may adversely affect access to care for millions of severely obese patients.
Evidence-Based Medicine↗
Single-cell recording from the brain of freely moving monkeys.
Single-cell recording from the brain of non-human primates has traditionally been performed in monkeys seated in a primate chair. However, this arrangement makes long-term recordings difficult, causes stress that may confound the data, and prevents the manifestation of natural behaviors. Extending our previous neurophysiological studies in non-human primates (Ludvig et al. Brain Res. Protocols 2000;5:75-85), we have developed a method for recording the electrical activity of single hippocampal neurons in freely moving squirrel monkeys (Saimiri sciureus). The recording sessions lasted for up to 6 h, during which the monkeys moved freely around on the walls and the floor of a large test chamber and collected food pellets. Stable action potential waveforms were readily kept throughout the sessions. The following factors proved to be critical in this study: (a) selecting squirrel monkeys for the experiments, (b) using a driveable bundle of microwires for the recordings, (c) using a special recording cable, (d) implanting the microwires into the brain without causing neurological deficits, and (e) running the recording sessions in a special test chamber. The described method allows long-term extracellular recordings from the brain of non-human primates, without the stress of chairing, during a wide range of natural behaviors. Using this model, new insights can be obtained into the unique firing repertoire of the neurons of the primate brain.
Animals↗
Morbidity of severe obesity.
Although obesity is an easy diagnosis to make, its etiologies, pathophysiology, and symptomatology are extraordinarily complex. Progress in surgical technique and anesthesiological management has substantially improved the safety of performing operations on the severely obese in the last 20 years. These improvements have occurred more or less empirically, without a full understanding of etiology or pathophysiology, although this has advanced concomitantly with improvements in practice. This review has attempted to provide a framework to facilitate progress in the neglected areas of patient selection and choice of operation, in an effort to improve long-term outcome. Despite the disparate etiologies of obesity and its diverse comorbidities and complications, there are unifying interdependent pathogenetic mechanisms of great relevance to the practice of antiobesity surgery. The rate of eating, whether driven by HPA dysfunction, ambient stress, or related hereditary susceptibility factors including the increased energy demands of an expanded body fat mass, participates in a cycle that results in disordered satiety (see Fig. 3). This leads to substrate overload, causing extensive metabolic abnormalities such as atherogenesis, insulin resistance, thrombogenesis, and carcinogenesis. This interpretation of the pathophysiology of obesity ironically accords with the original meaning of the word obesity: "to overeat." The ultimate solution to the problem of obesity--preventing it--will not be forthcoming until the food industry is forced to lower production and change its marketing strategies, as the liquor and tobacco industries in the United States were compelled to do. This cannot occur until the large and fast-growing populations of industrialized nations become educated in the personal implications of the energy principle. Regardless of whether school curricula are modified to prioritize health education, the larger problems of cultural and economic change remain for the groups most susceptible to obesity. In this context, antiobesity surgery will continue to thrive, especially in the absence of effective alternatives.
Comorbidity↗
Hypothalamic-pituitary-adrenal axis function and the metabolic syndrome X of obesity.
Obesity has negative health consequences related to fat distribution, particularly the central or visceral accumulation of fat. The major complications associated with visceral obesity, termed the "Metabolic Syndrome of Obesity," or "Syndrome X," are type II diabetes, hypertension, and dyslipidemia. As with certain mood disorders, the syndrome may be a consequence of neuroendocrine perturbations typically associated with chronic stress. Our work with bonnet macaque monkeys provides an animal model for the relationship between early stress, behavioral and hypothalamic-pituitary-adrenal (HPA) axis dysregulation, and Syndrome X. During their infant's first half-year, mothers face a variable foraging demand (VFD), in which ample food varies unpredictably in the difficulty of its acquisition, and the offspring show persistent abnormalities in systems known to modulate stress and affective regulation. Early work on the bonnet macaque noted the emergence of a sample of spontaneously obese subjects as they matured. Using the VFD model, the current study showed that there was a clear relationship between early cerebrospinal fluid corticotropin-releasing factor levels and subsequently measured body mass index, supporting the hypotheses regarding the interactive roles of early experience and HPA axis dysregulation in the ontogeny of both metabolic and mood disorders.
Journal Article↗
Metabolic correlates of eating behavior in severe obesity.
BACKGROUND: The benefit of spreading energy intake over many small meals ('nibbling') rather than few large ones ('gorging') for control of blood glucose, serum lipids and body fat accretion has been known for 60 y, but the mechanisms are poorly understood. Men exhibit more of a gorging eating pattern than women and are also more prone to the metabolic complications of obesity, as are women with a 'male', central distribution of adipose tissue. We have shown correlations between central fat distribution, and other components of the metabolic 'Syndrome X' and fatty infiltration of the liver. Here we study relationships between eating rate and fat distribution and test the hypothesis that gorging might be associated with fatty liver. SUBJECTS AND METHODS: In 30 non-alcoholic, non-diabetic, severely obese women (body mass index, BMI=47+/-1 kg/m(2); mean+/-s.e.m.) with a mean age of 36+/-1 y and 16 men (BMI: 52+/-3) age 38+/-2 y, who were candidates for anti-obesity surgery, we measured eating rate using an eating monitor, and fat distribution by the waist-hip circumference ratio (WHR). In addition in the 17 women and 11 men who had surgery, serum lipids were analyzed and routine liver biopsies were evaluated for steatosis by a pathologist blinded to the conditions of the study. RESULTS: Men ate significantly faster than women (188+/-28 vs 123+/-9 g/min; P<0.01), and had more liver fat (score: 2.7+/-03 vs 1.5+/-0.3; P<0.01), with no statistically significant sex differences in s-cholesterol or s-triglycerides. Eating rate correlated with WHR (r=0.46; P<0.01, n=46), liver fat (r=0.55; P<0.01), and s-triglycerides (r=0.42; P<0.05) adjusting for sex. Liver fat correlated with WHR (r=0.50; P<0.05), s-triglycerides (r=0.70; P<0.01) and s-cholesterol (r=0.50; P<0.05), while there were no significant correlations with BMI or body weight. In multivariate analysis eating rate (32%), meal size (8%) and WHR (6%) contributed 46% of the variance in liver fat. CONCLUSION: We showed increased eating rates in severely obese men and women with central fat distribution. Furthermore, increased eating rates were associated with fatty liver and elevated serum lipids. Eating rate in severely obese women and men may be a determinant of the metabolic syndrome.
Adipose Tissue↗
Relationships between tamoxifen use, liver fat and body fat distribution in women with breast cancer.
Tamoxifen is a nonsteroidal anti-estrogenic drug used for adjuvant treatment of breast cancer and recently as a chemopreventative agent for breast cancer and, on an investigational basis, for other cancers. To date there are case reports of hypertriglyceridemia and fatty liver disease in tamoxifen users. Fatty liver is associated with visceral obesity and other components of the metabolic syndrome. Here we evaluated steatosis and adipose tissue distribution by CT scan in a cross-sectional study of 32 women on tamoxifen and 39 control women. Tamoxifen users had more visceral adipose tissue (VAT) and more liver fat than controls. This is the first study to demonstrate that fatty liver and intra-abdominal fat accumulation are common in breast cancer patients receiving tamoxifen. Prospective studies of tamoxifen should monitor metabolic changes in obese women with or without breast cancer.
Adipose Tissue↗
Selection of patients for anti-obesity surgery.
Obesity is a disease with many comorbidities, some of which increase perioperative risk and most of which are improved or even cured by weight loss effectively achieved by surgery. Since anti-obesity surgery is "behavioral surgery", outcome is independent of the technical performance of the operation and patient selection is critical. Pre- and postoperative patient education is more important than in other gastrointestinal surgery. For example, knowledge of the "Rules of eating" and the "Rules of vomiting" are essential for outcome of gastric restrictive surgery. Indications for bariatric surgery are evolving as safety is increasing and more long-term data unequivocally demonstrate its effectiveness, leading to adjustments downward in body mass index and minimum age. However, outcome predictors are lacking, though it is recognized that patient knowledge, psychosocial adaptation and motivational factors including secondary gain and other benefits to remaining obese are important. Discrepancies between patients' weight goals, "ideal" or healthy weight for post-obese individuals and realistic weight loss based on body composition and energy balance, contribute to subjective assessment of quality of life after bariatric surgery. Well-designed observational studies rather than randomized trials, which are both ethically and scientifically flawed, are needed to improve patient selection. Until valid outcome predictors have been identified, a staged approach to bariatric surgery entailing long-term reoperation rates of up to 30% will prevail.
Body Mass Index↗
A pilot study analyzing PSA, serum testosterone, lipid profile, body mass index and race in a small sample of patients with and without carcinoma of the prostate.
Androgens, diet, race and obesity are thought to play some roles in the pathogenesis of prostate cancer. We wanted to evaluate if there were any inter-relationships between prostate specific antigen (PSA), serum testosterone, serum cholesterol, HDL, triglycerides, body mass index (BMI) and race, in older patients with and without prostate cancer (CaP). We evaluated 308 patients referred to urologists in private practice offices and clinics with and without prostate cancer with regard to race, serum PSA, age, serum testosterone, full lipid profile, height and weight, and stage of cancer. We used multivariate analysis, Fisher's exact test and t-tests as well as logistic regression analysis. Data was analyzed using SPSS computer software, and P-values<0.05 were considered statistically significant. Significantly higher levels of serum testosterone were found in black men with CaP than black men without CaP (526+/-28 vs 404+/-19, respectively.) We also found significantly higher levels of serum testosterone in white men with CaP than white men without CaP (409+/-20 vs 302+/-14, respectively, P<0.05). HDL was higher in black men than white men, and triglycerides were higher in white men than black men. Cholesterol was similar across all groups, but BMI was highest in white men with CaP. We also found a significant association between BMI and pathological stage of prostate cancer patients among both black and white men (P<0.05). Our study demonstrated that black men who developed CaP had higher serum testosterone levels, on average, than white men who developed CaP. Furthermore, BMI was highest in white men developing CaP compared to black men, but we found a significant association between pathological stage and BMI in both black and white patients. Although it is controversial whether obesity is considered to be a risk factor for prostate cancer, this small pilot study suggests that BMI may play a role in the progression of the disease once it is established.Prostate Cancer and Prostatic Diseases (2001) 4, 101-105
Journal Article↗
Delivering drugs, via microdialysis, into the environment of extracellularly recorded hippocampal neurons in behaving primates.
Hippocampal neurons in primates have been extensively studied with electrophysiological and neuroanatomical methods. Much less effort has been devoted to examining these cells with contemporary pharmacological techniques. Therefore, we modified a recently developed integrative technique (N. Ludvig, P.E. Potter, S.E. Fox, Simultaneous single-cell recording and microdialysis within the same brain site in freely behaving rats: a novel neurobiological method, J. Neurosci. Methods 55 (1994) 31-40 [9] ) for cellular neuropharmacological studies in behaving monkeys. A driveable microelectrode-microdialysis probe guide assembly was implanted stereotaxically into the left hippocampus of squirrel monkeys (Saimiri sciureus) under isoflurane anesthesia. The assembly was covered with a protective cap. After 3 weeks of postsurgical recovery and behavioral training, the experimental subject was seated in a primate chair. For 4-5 h, single-cell recording and microdialysis were simultaneously performed in the hippocampal implantation site. The technique allowed the recording of both complex-spike cells and fast-firing neurons without the use of head restraint. The control microdialysis solution, artificial cerebrospinal fluid (ACSF), was replaced with either 1 M ethanol or 500 microM N-methyl-D-aspartate (NMDA) for 10-30 min intervals. The ethanol perfusions principally suppressed the firing of the neurons in the dialysis area. The NMDA perfusions initially increased the firing of local neurons, then caused electrical silence. These drug delivery/cell recording sessions were performed with 1-4 day intersession intervals over a 1-month period. The described method provides a tool to elaborate the pharmacology of primate hippocampal neurons during behavior and without the confounding effects of systemic drug administrations.
Animals↗
Obesity potentiates AOM-induced colon cancer.
Obesity and diet affect the incidence and severity of various types of cancer, including colon cancer. It is not known whether obesity, independent of diet, is a risk factor for colon adenocarcinoma. We used azoxymethane (AOM) to induce colon cancer in mature genetically obese male Zucker rats (fa/fa) on low-fat crude diet (LFC, 10% fat) and their lean counterparts (Fa/fa and Fa/fa) on high-fat crude diet (HFC, 40% fat) for three months. At death visible tumors, histopathology, and colonic aberrant crypt (AC) formation were studied by blinded investigators. At death the obese animals were heavier (719 +/- 19 g; mean +/- SEM) than lean animals regardless of diet or genotype (Fa/fa-LFC:451 = 6 g; Fa/fa-HFC:441 +/-10 g; Fa/Fa-HFC:412 +/- 9 g; P < 0.001 vs fa/fa by ANOVA). All AOM-treated rats developed AC, compared to none of the saline-injected controls. Macroscopic adenocarcinoma developed in 8/9 obese rats on LFC (P < 0.001), compared to none in lean rats regardless of diet. Obese rats had significantly more AC (876 +/- 116) than any of the lean rats (Fa/fa-LFC:550 +/- 99; Fa/fa-HFC:325 +/- 37; Fa/Fa-HFC:360 +/- 36; P < 0.05 vs fa/fa). We conclude that obesity more than exposure to high-fat diet was associated with colon carcinogenesis in these rats.
Adenocarcinoma↗
Associations of leptin, insulin resistance and thyroid function with long-term weight loss in dieting obese men.
OBJECTIVE: The aim of the present study was to identify predictors of weight loss in obese men participating in a 2-year behaviour modification programme. DESIGN: Longitudinal, clinical intervention study of a behaviour modifying weight loss program. SETTING: University Hospital, Stockholm, Sweden. SUBJECTS: Forty-four obese men (age, 42.7 +/- 1.1 years: BMI, 37.1 +/- 0.6 kg m(-2), mean +/- SEM) followed for 2 years. INTERVENTIONS: Behaviour modification weight loss programme. MAIN OUTCOME MEASURES: Associations between plasma leptin and thyroid function tests, insulin resistance by homeostatic model assessment (HOMA), dietary recall and anthropometrically determined body composition. RESULTS: At baseline, there were significant correlations between plasma leptin and body mass index (BMI), fat-free mass (FFM) and insulin resistance. Median weight loss over 2 years was 4.9 kg (range, -27.2 to +11.9). Baseline serum leptin concentrations adjusted for BMI (leptin/BMI ratio) were significantly correlated with 2-year weight change (r = 0.34, P = 0.04). A subset of seven of the 44 men gained weight over the 2 years. These 'gainers' differed significantly in initial leptin/BMI ratio (0.62 +/- 0.07) compared with the 37 'losers' (0.42 +/- 0.03, P < 0.05). In a multiple regression model, baseline leptin, insulin and age predicted 22% of the variance in weight change with no additional significant contribution from BMI, FFM, waist:hip ratio, thyroid function tests or energy intake. There was a strong correlation between the change in leptin concentrations and the change in insulin resistance from baseline to 2-year follow-up (r = 0.54; P < 0.001). CONCLUSION: Baseline plasma leptin concentrations predicted long-term weight loss. Inappropriate leptin secretion or disposal, corrected for BMI, was associated with failure to maintain weight loss in obese men in a behaviour modification weight loss programme.
Adult↗
Subcutaneous lipectomy causes a metabolic syndrome in hamsters.
The insulin resistance syndrome X is related to excess intra-abdominal adipose tissue. With lipectomy of >50% of subcutaneous adipose tissue (SQAT) in nonhibernating, adult female Syrian hamsters on high-fat (HF; 50 calorie%) diet and measurements of oral glucose tolerance, oral [(14)C]oleic acid disposal, serum triglycerides, serum leptin, liver fat, perirenal (PR) adipose tissue cellularity, and body composition, we studied the role of SQAT. Sham-operated (S) animals on HF or low-fat (LF; 12.5 calorie%) diets served as controls. After 3 mo there was no visible regrowth of SQAT but HF diet led to similar levels of body weight and body fat in lipectomized and sham-operated animals. Lipectomized (L) animals had more intra-abdominal fat as a percentage of total body fat, higher insulinemic index, a strong trend toward increased liver fat content, and markedly elevated serum triglycerides compared with S-HF and S-LF. Liver and PR adipose tissue uptake of fatty acid were similar in L-HF and S-HF but reduced vs. S-LF, and were inversely correlated with liver fat content and insulin sums during the oral glucose tolerance test. In summary, lipectomy of SQAT led to compensatory fat accumulation implying regulation of total body fat mass. In conjunction with HF diet these lipectomized hamsters developed a metabolic syndrome with significant hypertriglyceridemia, relative increase in intra-abdominal fat, and insulin resistance. We propose that SQAT, via disposal and storage of excess ingested energy, acts as a metabolic sink and protects against the metabolic syndrome of obesity.
Adipose Tissue↗
Autocrine regulation of human preadipocyte migration by plasminogen activator inhibitor-1.
One of the initial stages of adipogenesis is migration of preadipocytes of mesenchymal origin into cell clusters to form primitive fat organs. The serine protease inhibitor plasminogen activator inhibitor-1 (PAI-1) is synthesized and released from human adipose tissue ex vivo and regulates smooth muscle and endothelial cell migration in vitro, but its role in adipose tissue is not known. We investigated the role of PAI-1 in cultures of human preadipocytes from men and women of various ages and body mass indexes. Human preadipocytes expressed the messenger ribonucleic acid for PAI-1 and released significant quantities of PAI-1 protein into the medium. As PAI-1 regulates motility through the interaction of vitronectin with its receptor, the integrin alphaVbeta3, we identified this receptor in human preadipocytes. Flow cytometric analysis indicated that human preadipocytes express the vitronectin receptor alphaVbeta3 in a similar pattern as human umbilical vein endothelial cells. Functional studies indicated that active, but not latent, PAI-1 inhibited preadipocyte attachment to vitronectin with an IC(50) of 13.3 nmol/L, and preincubation of vitronectin-coated Transwells with active PAI-1 prevented preadipocyte migration. Vitronectin was identified in homogenates of the stromal-vascular fraction of human adipose tissue, but was absent from human adipocytes and cultured preadipocytes. These data indicate that human preadipocyte migration is regulated through the endogenous expression of PAI-1 and alphaVbeta3 integrin, a novel autocrine mechanism for potentially regulating cell cluster formation in adipogenesis.
Adipocytes↗
The role of obesity and diet in urological carcinogenesis.
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Aging↗
Development of a human adipocyte synthetic polymer scaffold.
Because of the need for methods for successful transplantation of autologous fat, the differentiation of human preadipocytes on surgical mesh coated with various extracellular matrix components was investigated. Biopsy specimens of human adipose tissue were collected from seven different patients and were subjected to collagenase digestion and selective filtration, resulting in primary cultures of human preadipocytes. Fluortex monofilament-expanded polytetrafluoroethylene (52-/xm pore size) was as a template for coating with either human collagen, albumin, or fibronectin, followed by sodding with established cultures of human preadipocytes. Sodding efficiency on the different matrices was determined by trypsinization of attached cells at different time periods. Preadipocytes did not attach to uncoated polytetrafluoroethylene, but did attach to protein-coated mesh, and in a variable manner. Fibronectin-coating resulted in the highest efficiency of sodding, with differentiation of preadipocytes to adipocytes as assessed by scanning electron -microscopy and conventional Oil Red O staining. Similar results were achieved by using rat (n = 6) perirenal adipose tissue. This new method of adipocyte scaffolding may be used for improving soft-tissue augmentation and serving as a delivery system for growth factors important in wound healing.
Adipocytes↗
Angiotensin II receptors in human preadipocytes: role in cell cycle regulation.
The role of angiotensin II (AII) in human preadipocyte physiology has been investigated in primary cultures from human adipose tissue. Receptor binding studies indicated that human preadipocytes express a high affinity AII binding site of the AT1 subtype, as binding of 125I-labeled [Sar1,Ile8]AII was rapid, saturable, and specific. As AII has previously been demonstrated to affect the cell cycle in adrenal and cardiac cells, the effect of AII on regulation of cycle progression was examined in human preadipocytes. Stimulation of preadipocytes with AII resulted in G1 phase progression of the cell cycle, as determined by flow cytometric analysis. AII treatment was associated with induction of expression of the messenger RNA for the cell cycle regulatory protein cyclin D1 in a dose-dependent manner. Pretreatment of cells with subtype-selective AT receptor ligands before AII stimulation indicated that the cyclin response was mediated via the AT1 receptor. The identity of the cells as preadipocyte was verified by culture in a defined differentiation medium, observing both leptin message expression and triglyceride accumulation by flow cytometry. These findings indicate that AII has early, receptor-mediated effects on cell cycle progression in human preadipocytes that may contribute to differentiation to the adipocyte phenotype.
1-Sarcosine-8-Isoleucine Angiotensin II↗
Liver pathology and the metabolic syndrome X in severe obesity.
The metabolic syndrome X, characterized by insulin resistance, dyslipidemia, hypertension, and a male, visceral distribution of adipose tissue, is associated with increased morbidity and mortality from several prevalent diseases, such as diabetes, cancers, myocardial infarction, and stroke. Because the liver has a central role in carbohydrate, lipid, and steroid metabolism, we investigated the relationships between liver pathology and the metabolic syndrome. Blood chemistry, anthropometry (waist/hip circumference ratio), and intraoperative routine knife biopsies of the liver were obtained in 551 (112 men) severely obese patients (body mass index, 47 +/- 9; mean +/- SD) undergoing antiobesity surgery. Steatosis was found in 86%, fibrosis in 74%, mild inflammation or steatohepatitis in 24%, and unexpected cirrhosis in 2% (n = 11) of the patients. The risk of steatosis was 2.6 times greater in men than in women (P < 0.0001). With each addition of 1 of the 4 components of the metabolic syndrome, elevated waist/hip ratio, impaired glucose tolerance, hypertension, and dyslipidemia, the risk of steatosis increased exponentially from 1- to 99-fold (P < 0.001). Fibrosis correlated with steatosis (r = 0.56; P < 0.0001), whereas patients with diabetes or impaired glucose tolerance had a 7-fold increased risk of fibrosis (P < 0.0001). Diabetes, steatosis, and age were all significant indicators of cirrhosis, whereas inflammation was only associated with age. We conclude that the metabolic syndrome via impaired glucose tolerance is strongly correlated with steatosis, fibrosis, and cirrhosis of the liver.
Adult↗